DNA is a complex macromolecule whose activities are influenced by its base composition and base modification, as well as helical orientation. Bacterial DNA, as well as certain synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG sequences, can induce proliferation and immunoglobulin production by murine B cells. Unmethylated CpG dinucleotides are more frequent in the genomes of bacteria and viruses than vertebrates. Studies have suggested that immune recognition of these motifs may contribute to the host's innate immune response. (Klinman et al., Proc. Natl. Acad. Sci. USA 93:2879, 1996; Yi et al., J. Immun. 157:5394, 1996; Liang et al., J. Clin. Invest. II 9:89, 1996; Krieg et al., Nature 374:546, 1995).
A CpG oligodeoxynucleotide (ODN) is an oligodeoxynucleotide including a CpG motif, wherein the pyrimidine ring of the cytosine is unmethylated. Three types of CpG ODNs have been identified: C-type, K-type and D-type ODNs. Generally, CpG ODNs range from about 8 to 30 bases in size. D- and K-type nucleic acid sequences have been described in the published PCT Publication No. WO 98/18810A1 (K-type) and published PCT Publication No. WO 00/61151 (D-type). Generally D ODNs can stimulate a cellular immune response, while K ODNs can stimulate a humoral immune response.
Unmethylated CpG motifs, including both D-type ODNs and K-type ODNs, are recognized by the Toll-like receptor 9 (TLR9) expressed on immune cells (such as B cells, macrophages, and dendritic cells). The CpG DNA is taken up by an endocytic/phagocytic pathway. It is known that the interaction of CpG ODN with TLR9 triggers recruitment of a MyD88 adaptor molecule, activation of an IL-1R kinase-1 and other factors, resulting in the production of cytokines (see Latz et al., Nat. Immunol. 5:190-8, 2004).
CpG ODNs can be used to induce an immune response. Thus, they have been found to have many uses, such as to induce an immune response to antigens, in the production of vaccines, and as adjuvants. It would be advantageous to be able to alter the uptake of CpG ODN by cells, in order to alter the immune response produced by these oligonucleotides. Methods to alter the uptake and subsequent immune activation triggered by CpG ODN are disclosed herein.